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Synergy between 15-...
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Ha, Van ThaiDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana, Slovenia
(author)
Synergy between 15-lipoxygenase and secreted PLA(2) promotes inflammation by formation of TLR4 agonists from extracellular vesicles
- Article/chapterEnglish2020
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2020-09-24
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The National Academy of Sciences,2020
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LIBRIS-ID:oai:DiVA.org:oru-86046
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-86046URI
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https://doi.org/10.1073/pnas.2005111117DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Funding Agencies:H2020 Marie Sklodowska-Curie Innovative Training Networks project TOLLerant 642157Slovenian Research Agency - Slovenia P4-0176 J3-9257
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Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.
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Lainšček, DuškoDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia
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Gesslbauer, BerndInstitute of Pharmaceutical Sciences, University of Graz, Graz, Austria
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Jarc-Jovičić, EvaDepartment of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
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Hyötyläinen, Tuulia,1971-Örebro universitet,Institutionen för naturvetenskap och teknik(Swepub:oru)tihn
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Ilc, NejcFaculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia
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Lakota, KatjaDepartment of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Mathematics, Natural Science and Information Technologies, University of Primorska, Koper, Slovenia
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Tomšič, MatijaDepartment of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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van de Loo, Fons A. J.Department of Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Bochkov, ValeryInstitute of Pharmaceutical Sciences, University of Graz, Graz, Austria
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Petan, ToniDepartment of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
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Jerala, RomanDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia
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Manček-Keber, MatejaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia
(author)
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Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia; Excellent NMR Future Innovation for Sustainable Technologies (EN-FIST), Centre of Excellence, Ljubljana, Slovenia
(creator_code:org_t)
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In:Proceedings of the National Academy of Sciences of the United States of America: The National Academy of Sciences117:41, s. 25679-256890027-84241091-6490
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Ha, Van Thai
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Lainšček, Duško
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Gesslbauer, Bern ...
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Jarc-Jovičić, Ev ...
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Hyötyläinen, Tuu ...
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Ilc, Nejc
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Lakota, Katja
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Tomšič, Matija
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Petan, Toni
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Jerala, Roman
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